Aspects of destructive and degenerative diseases of early life

Abstract

The chronology of fetal and neonatal HIE In comparison to the relatively stereotypical consequences of noxious events in the mature brain, the pathology resulting from any insult, and particularly hypoxia-ischaemia, during the extended perinatal period is extraordinarily variable. This is a critical period for rapid developmental change and brain growth, with an 18-fold increase in brain weight and a multiplicity of organisational events, such as neuronal differentiation, gliogenesis and myelination occurring alongside maturational changes in tissue responses, including an optimal capacity for plasticity and repair. Against this rapidly changing background, the effects of any hypoxic-ischaemic insult are somewhat time-locked. In this overview, aspects of these pathological lesions will be considered in relation to developmental changes influencing their pathogenesis. Spinal muscular atrophy: more than the motor neuron Proximal recessively inherited spinal muscular atrophy (SMA), the second most frequently lethal genetic disorder in childhood, is characterised by progressive degeneration of bulbo-spinal lower motor neurons and concomitant skeletal muscle atrophy. The three clinical forms of childhood onset SMA [acute early onset severe type 1 Werdnig-Hoffman disease (WH), chronic intermediate type 2, and chronic mild type 3 or Kugelberg-Welander] are caused by abnormally low levels of the ubiquitous protein ‘survival of motor neuron’ (SMN) resulting from a combination of homozygous deletions or mutations of the telomeric copy of the gene SMN1 on chromosome 5q and the presence of one or more copies of SMN2, an almost identical but partially functional centromeric copy, unique to man, which may modulate the clinical phenotype. Now that we know the genetic basis, and have a genetically engineered mouse model, it is time to re-evaluate the pathology. Available morphological data in genetically proven cases is limited, but suggests that earlier pathological reports were accurate and show a wider spectrum of pathology than has generally been appreciated, particularly involving the thalamus and dorsal root ganglia. In the most severe fetal onset cases which have the lowest copy number of SMN2, neurodegenerative changes encompass many other regions suggesting differential thresholds to reduction in SMN protein level among different cell populations.